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OBJECTIVES: To describe the clinical features and oncologic outcome for cats with primary rib tumours. MATERIALS AND METHODS: Medical records for cats with surgically treated primary rib tumours from six veterinary referral centres were reviewed. Signalment, preoperative clinical signs, reconstruction technique, and surgical and oncologic outcome were retrieved from medical records or by telephone interview with owners and/or referring veterinarians. RESULTS: Of the eight cats with primary rib tumours, three had hemangiosarcoma, two had osteosarcoma and one cat each had chondrosarcoma, osteochondroma and osteoma. The size of the primary rib mass ranged from 2 × 2 × 1.6 cm to 9 × 7 × 7.5 cm. Three minor and one major complication developed during the immediate post-operative period. Surgery consisted of thoracic wall resection in all cats. All animals survived the procedure and the median time to discharge was 3 days. The survival time for benign tumours was 150 (case 5) and 466 (case 4) days, while for malignant tumours ranged from 105 to 550 days (cases 1 to 3, cases 6 to 8). CLINICAL SIGNIFICANCE: Hemangiosarcoma and osteosarcoma were the most represented primary rib tumours in this cohort of cats. Wide surgical excision and adjuvant chemotherapy is recommended for cats with hemangiosarcoma and osteosarcoma, but the prognosis remains guarded. Prognosis appears to be fair for the other tumour types.
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This study shows clinical efficacy and safety profile of an off-label use of caplacizumab for the treatment of immune-mediated thrombotic thrombocytopenic purpura in a middle-aged obese male patient manifesting aphasia, weakness and unconsciousness. Routine blood tests revealed haemolytic anaemia, severe thrombocytopenia (platelet count=20×109/L) and moderate creatinine increase. Diagnosis was based on the clinical judgement and laboratory determinations (undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies). The patient underwent plasma-exchange and an adjunctive treatment with prednisone (1mg/Kg/day), but the occurrence of a refractory and exacerbated form of disease suggested also using rituximab (375mg/m2 weekly for 4 weeks) and caplacizumab as salvage treatments. The caplacizumab was given at 10mg/day subcutaneously without the first intravenous bolus. Because von Willebrand factor inhibition, platelet count recovery and remission of symptoms were achieved, use of caplacizumab with this scheme appeared to be as effective as the approved one. Although this is an off-label use, this case highlights the potential of this new treatment, in terms of drug's efficacy and safety.
Assuntos
Uso Off-Label , Púrpura Trombocitopênica Trombótica , Anticorpos de Domínio Único , Proteína ADAMTS13 , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Troca Plasmática , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Anticorpos de Domínio Único/uso terapêuticoRESUMO
OBJECTIVE: To describe the use of a caudal superficial epigastric flap in combination with a full-thickness oral mucosal/submucosal graft for single-stage reconstruction of extensive preputial defects in dogs. MATERIALS AND METHODS: Medical records of dogs with extensive preputial defects either of traumatic origin or derived from tumour excision were reviewed. In all dogs, the prepuce was reconstructed using a full-thickness oral mucosal/submucosal graft combined with a caudal superficial epigastric axial pattern flap during a single surgical procedure. Outcome was assessed by routine clinical examinations for 6 months postoperatively, and through telephone follow-up thereafter. RESULTS: Six dogs were included. The caudal superficial epigastric axial pattern flap healed without complications in all dogs, while the full-thickness oral mucosal/submucosal graft failed in one dog. In this individual the skin flap underwent contracture 30 days after surgery and preputial advancement was required. One dog showed postoperative discomfort during urination, which was successfully managed with a Foley catheter and analgesic administration. Three dogs developed paraphimosis at 30, 80 and 90 days, respectively, and required further surgery. Long-term results were good in all dogs. CLINICAL SIGNIFICANCE: The use of a full-thickness oral mucosal/submucosal graft combined with a caudal superficial epigastric axial pattern flap is feasible for single-stage preputial reconstruction in dogs. Attention should be paid to create a sufficiently large preputial opening, in order to prevent paraphimosis.
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Doenças do Cão/cirurgia , Procedimentos de Cirurgia Plástica/veterinária , Procedimentos Cirúrgicos Urológicos Masculinos/veterinária , Animais , Cães , Masculino , Mucosa Bucal/transplante , Parafimose/cirurgia , Parafimose/veterinária , Complicações Pós-Operatórias/veterinária , Procedimentos de Cirurgia Plástica/métodos , Transplante de Pele/métodos , Transplante de Pele/veterinária , Retalhos Cirúrgicos/veterinária , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos Masculinos/métodosRESUMO
Klotho is an anti-aging factor mainly produced by renal tubular epithelial cells (TEC) with pleiotropic functions. Klotho is down-regulated in acute kidney injury in native kidney; however, the modulation of Klotho in kidney transplantation has not been investigated. In a swine model of ischemia/reperfusion injury (IRI), we observed a remarkable reduction of renal Klotho by 24 h from IRI. Complement inhibition by C1-inhibitor preserved Klotho expression in vivo by abrogating nuclear factor kappa B (NF-kB) signaling. In accordance, complement anaphylotoxin C5a led to a significant down-regulation of Klotho in TEC in vitro that was NF-kB mediated. Analysis of Klotho in kidneys from cadaveric donors demonstrated a significant expression of Klotho in pre-implantation biopsies; however, patients affected by delayed graft function (DGF) showed a profound down-regulation of Klotho compared with patients with early graft function. Quantification of serum Klotho after 2 years from transplantation demonstrated significant lower levels in DGF patients. Our data demonstrated that complement might be pivotal in the down-regulation of Klotho in IRI leading to a permanent deficiency after years from transplantation. Considering the anti-senescence and anti-fibrotic effects of Klotho at renal levels, we hypothesize that this acquired deficiency of Klotho might contribute to DGF-associated chronic allograft dysfunction.
Assuntos
Complemento C5a/farmacologia , Função Retardada do Enxerto/etiologia , Glucuronidase/metabolismo , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Traumatismo por Reperfusão/etiologia , Injúria Renal Aguda/cirurgia , Animais , Western Blotting , Células Cultivadas , Função Retardada do Enxerto/metabolismo , Função Retardada do Enxerto/patologia , Glucuronidase/genética , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Técnicas Imunoenzimáticas , Fatores Imunológicos/farmacologia , Proteínas Klotho , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Transplante HomólogoRESUMO
Loosening of the acetabular cup is one of the most common complications following total hip replacement and has an incidence rate of 1.8% to 36.8%. The objective of this study was to describe the surgical technique for the application of a cementless acetabular component specifically designed for treatment of cup loosening and preliminary clinical experience. The Kyon revision cup is composed of two components; the first is a perforated titanium outer shell with holes for 2.4 mm titanium screws, which is impacted into the acetabulum after removal of the loose cup and reaming of the acetabulum. It is secured with a variable number of screws. The second component is an inner plain titanium cup with an ultra-high-molecular-weight polyethylene insert, which is impacted into the outer shell to obtain press-fit stability. This revision cup was used in 31 dogs with cup loosening and a minimum follow-up period of six months. There were four intra-operative complications and two postoperative complications. The main intra-operative complication was difficulty inserting the inner cup into the outer shell. Postoperative complications included craniodorsal hip luxation in one dog, which was successfully managed, and cup loosening in another dog, which required explantation of the prosthesis. The main advantage of the revision cup appears to be increased implant stability afforded by screw fixation. Our initial clinical results in 31 dogs were promising; all but one dog had a successful clinical outcome.
Assuntos
Acetábulo/cirurgia , Artroplastia de Quadril/veterinária , Doenças do Cão/cirurgia , Prótese de Quadril/veterinária , Falha de Prótese , Animais , Artroplastia de Quadril/instrumentação , Cães , Feminino , Masculino , Complicações Pós-Operatórias/cirurgia , Desenho de PróteseRESUMO
The purpose of this investigation was to evaluate the effectiveness of posterior pharyngeal and nasopharyngeal swabs in identifying and quantifying meningococcal carriage. Two swab samples were obtained from 564 healthy adolescents aged 15-19 years, the first taken from the posterior pharyngeal wall through the mouth and the second through the nose. Bacterial genomic DNA was extracted and screened for Neisseria meningitidis by means of two separate singleplex real-time polymerase chain reactions (real-time PCRs) in order to identify the CtrA and sodC genes. Subsequently, N. meningitidis-positive samples underwent a further singleplex real-time PCR in order to determine the N. meningitidis serogroup, and the DNA was quantified by means of standard curves. Thirty-seven subjects (6.6 %) were found to be carriers of N. meningitidis. The most frequently carried serogroup was serogroup B (15 cases, 40.5 %); serogroups A, Y, X, W135 and Z were found in, respectively, two (5.4 %), five (13.5 %), four (10.8 %), three (8.1 %) and one subject (2.7 %); the serogroup was not identified in seven cases. The detection of carrier status was significantly more frequent using posterior pharyngeal swabs (5.3 % vs. 2.1 %; p = 0.004), which also contained a significantly larger number of N. meningitidis genomic copies (4.91 ± 1.39 vs. 2.50 ± 0.8 log10 genomic copies/mL; p < 0.001). Posterior pharyngeal swabs seem to be better than nasopharyngeal swabs for detecting N. meningitidis carriage in large-scale epidemiological studies because they identify a significantly larger number of pathogen carriers and recover a significantly larger amount of bacterial DNA.
Assuntos
DNA Bacteriano/análise , Infecções Meningocócicas/diagnóstico , Nasofaringe/microbiologia , Adolescente , Carga Bacteriana , Proteínas de Bactérias/genética , Portador Sadio/microbiologia , Técnicas e Procedimentos Diagnósticos , Feminino , Humanos , Masculino , Infecções Meningocócicas/microbiologia , Neisseria meningitidis/genética , Neisseria meningitidis/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
BACKGROUND: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma. OBJECTIVES: This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks. METHODS: An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (≥ 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h. RESULTS: A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.
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Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Inativadores do Complemento/uso terapêutico , Adolescente , Adulto , Idoso , Proteína Inibidora do Complemento C1/administração & dosagem , Proteína Inibidora do Complemento C1/efeitos adversos , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Acquired angioedema (AAE) with C1 inhibitor deficiency is often associated to B cell lymphoproliferative disorders or autoimmune diseases. We report a case of AAE associated with IgM anti-cardiolipin antibodies, with frequent edematous attacks, that disappeared completely after a slight immunosuppression and danazol therapy.
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Angioedema/imunologia , Anticorpos Anticardiolipina/sangue , Proteínas Inativadoras do Complemento 1/deficiência , Imunoglobulina M/sangue , Idoso , Angioedema/diagnóstico , Angioedema/tratamento farmacológico , Azatioprina/uso terapêutico , Proteína Inibidora do Complemento C1 , Danazol/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Ticlopidina/uso terapêutico , Resultado do TratamentoAssuntos
Proteínas Inativadoras do Complemento 1/administração & dosagem , Doenças em Gêmeos/tratamento farmacológico , Angioedema Hereditário Tipos I e II/complicações , Angioedema Hereditário Tipos I e II/tratamento farmacológico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Adulto , Proteína Inibidora do Complemento C1 , Feminino , Humanos , Recém-Nascido , Infusões Intravenosas , Trabalho de Parto , Masculino , Linhagem , Gravidez , Resultado da Gravidez , Gêmeos MonozigóticosRESUMO
BACKGROUND: Mental disorders are frequent in hemodialysis (HD) patients. Depression and anxiety along with physical co-morbidity affect quality of life (QOL). Uremia is associated with inflammation and release of cytokines by lymphomonocytes. Inflammatory cytokines are relevant in depression. The aim of this study was to assess the psychological alterations and QOL in HD patients, and to correlate them with pattern of cytokine production. PATIENTS: 30 HD patients and 20 subjects with CKD Stage I-II K-DOQI. Psychometric tests were administered: 1) Hospital Anxiety and Depression Scale (HADS) composed of an anxiety subscale (HADS-A) and a depression subscale (HADS-D); 2) Kidney Disease Quality of Life (KDQOL) modified, including a cognitive function subscale (KDQOL-CF). Whole blood samples collected at beginning of HD session were diluted with RPMI/heparin and incubated for 24 h in presence of lipopolysaccharide (LPS). IL-1Gamma, IL-6, TNF-alpha and IL-10 were assayed on supernatants and results were normalized per number of lymphomonocytes (ng/106 cells). RESULTS: A depressive mood was more frequent in HD patients (50%) than controls (20%, p < 0.0001). No difference for anxiety (HD = 43%, controls = 45%) was observed. QOL score was significantly lower in HD than controls (p = 0.006) and correlated inversely with HADS total, HADS-A and HADS-D (p < 0.0001). Albumin, Kt/V and phosphate were comparable in patients with or without anxiety or depression. Cytokine production was significantly higher in HD patients than controls (IL-1beta p = 0.05; IL-6 p = 0.010; TNF-alpha p < 0.0001; IL-10, p = 0.0019). HD patients with the HADS-A positive for anxiety showed higher IL-6 production (p = 0.026), while IL-1beta levels were not associated with symptoms of depression. KDQOL-CF correlated inversely with levels of IL-6, TNF-alpha and IL-10. CONCLUSIONS: HD patients have symptoms of depression and anxiety that negatively affect QOL. These symptoms are independent of the efficiency of dialysis and nutritional status. On the contrary, IL-6 is linked to the presence of psychological discomfort in these patients.
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Citocinas/sangue , Falência Renal Crônica/psicologia , Qualidade de Vida/psicologia , Diálise Renal/psicologia , Adulto , Idoso , Ansiedade/sangue , Ansiedade/psicologia , Depressão/sangue , Depressão/psicologia , Emoções , Feminino , Humanos , Inflamação/sangue , Inflamação/psicologia , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Mechanisms for human membranous glomerulonephritis (MGN) remain elusive. Most up-to-date concepts still rely on the rat model of Passive Heymann Nephritis that derives from an autoimmune response to glomerular megalin, with complement activation and membrane attack complex assembly. Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies against clusterin, C5b-9, and phosphorylated-protien kinase C (PKC) isoforms (pPKC). In vitro experiments were performed to investigate the role of clusterin during podocyte damage by MGN serum and define clusterin binding to human podocytes, where megalin is known to be absent. Clusterin, C5b-9, and pPKC-alpha/beta showed highly variable glomerular staining, where high clusterin profiles were inversely correlated to C5b-9 and PKC-alpha/beta expression (P=0.029), and co-localized with the low-density lipoprotein receptor (LDL-R). Glomerular clusterin emerged as the single factor influencing proteinuria at multivariate analysis and was associated with a reduction of proteinuria after a follow-up of 1.5 years (-88.1%, P=0.027). Incubation of podocytes with MGN sera determined strong upregulation of pPKC-alpha/beta that was reverted by pre-incubation with clusterin, serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDL-R antibodies and with specific ligands. These data suggest a central role for glomerular clusterin in MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.
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Clusterina/metabolismo , Glomerulonefrite Membranosa/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C/metabolismo , Adulto , Idoso , Biópsia , Proteínas Sanguíneas/farmacologia , Células Cultivadas , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Seguimentos , Glomerulonefrite Membranosa/patologia , Humanos , Masculino , Fosforilação , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Prognóstico , Proteína Quinase C beta , Receptores de LDL/metabolismoRESUMO
Chronic renal failure and haemodialysis patients are prone to develop encephalopathy. The causes of encephalopathy are often unclear. Clinical signs of encephalopathy in the uraemic patient often overlap with several other affections causing neurological disorders. Whenever basal ganglia are anatomically involved, movement disorders arise, including chorea. Some acute and chronic neurological syndromes associated with chronic uraemia have consistently been reported (uraemic encephalopathy, dialysis disequilibrium syndrome, dialysis dementia, nephroangiosclerosis neuropathy and ageing neuropathy). Other clinical conditions in which neurological involvement exists are not so frequent in both haemodialysis patients and in the general population (Wernicke's encefalopathy, Creutzfeldt-Jacob disease). Because of the non specific symptoms and the very heterogeneous aetiology, a careful physical examination should be performed in haemodialysis patients with clinical signs of encephalopathy and the main metabolic alterations should be sought; moreover, central nervous system imaging examination is often appropriate. In case of basal ganglia anatomical involvement, supported by findings of imaging techniques, it is necessary to evaluate individual causes of encephalopathy by means of more accurate tests including analysis of cerebro-spinal fluid, measurement of plasma levels of vitamin B components and laboratory tests searching for more uncommon diseases such as Huntington's chorea and Wilson's disease.
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Coreia/etiologia , Diálise Renal/efeitos adversos , Uremia/complicações , Idoso , Anemia Megaloblástica/complicações , Anemia Megaloblástica/tratamento farmacológico , Gânglios da Base/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias Metabólicas/complicações , Encefalopatias Metabólicas/diagnóstico , Corpo Estriado/patologia , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/terapia , Neuropatias Diabéticas/etiologia , Retinopatia Diabética/etiologia , Diagnóstico Diferencial , Resistência a Medicamentos , Disartria/etiologia , Eritropoetina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Hipertensão/complicações , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X , Uremia/terapia , Complexo Vitamínico B/uso terapêutico , Encefalopatia de Wernicke/diagnósticoRESUMO
UNLABELLED: Renal C3 synthesis in idiopathic membranous nephropathy: Correlation to urinary C5b-9 excretion. BACKGROUND: Complement activation plays a central pathogenetic role in idiopathic membranous nephropathy (IMN). Urinary excretion of C5b-9 correlates to the immunologic activity of this disease. Recently, renal cortical C3 gene expression has been described in several nephropathies. METHODS: The aim of this study was to investigate the renal C3 gene expression by in situ hybridization in IMN and to correlate it with histopathologic, pathophysiologic, and immunologic (urinary C5b-9) indices of disease activity. RESULTS: C3 was expressed in 77% of 22 renal biopsies of IMN patients, mainly at the cortical tubular and glomerular parietal epithelial cell levels. C3 protein synthesis by tubular cells was demonstrated by immunofluorescence. The intensity of C3 gene expression by both glomerular and tubulointerstitial compartments correlated with the glomerular stage of disease (P = 0. 0023 and P = 0.0214, respectively). Although no correlation was found with proteinuria, serum creatinine at renal biopsy time was strongly associated with renal C3 expression. IMN patients showed a trend of increased urinary C5b-9 levels, which correlated to C3 at the tubulointerstitial level (P = 0.0143). CONCLUSION: Renal C3 production, mainly at the tubular level, may be induced by urinary excretion of C5b-9 in IMN and may have a pathogenetic role in the tubulointerstitial damage that can be associated with this disease.
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Complemento C3/biossíntese , Complexo de Ataque à Membrana do Sistema Complemento/urina , Glomerulonefrite Membranosa/metabolismo , Rim/metabolismo , Adulto , Idoso , Complemento C3/genética , Feminino , Imunofluorescência , Expressão Gênica , Glomerulonefrite Membranosa/urina , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genéticaRESUMO
IgA nephropathy, the most common form of primary glomerulonephritis, progresses to terminal renal failure in about 25% of patients 10 years after the apparent clinical onset. Since its description in 1968 an intense research effort in order to clarify the pathogenetic mechanisms has involved the study of animal models of the disease. In this review we analyze the experimental work reported since 1979, when the first animal model of IgA nephropathy was published by Rifai et al. We also discuss the interplay between experimental data and relevant clinical observations. Finally, we report the new insights about the role played by cytokines and growth factors.
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Modelos Animais de Doenças , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/patologia , Animais , Autacoides/imunologia , Ativação do Complemento/imunologia , Citocinas/imunologia , Dieta/efeitos adversos , Progressão da Doença , Glomerulonefrite por IGA/imunologia , Substâncias de Crescimento/imunologia , Humanos , Imunidade nas Mucosas/imunologia , Falência Renal Crônica/etiologia , Viroses/complicaçõesAssuntos
Antioxidantes/farmacologia , Leucócitos Mononucleares/fisiologia , Membranas Artificiais , Diálise Renal , Vitamina E/farmacologia , Adulto , Celulose , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Via Alternativa do Complemento , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Glomerular C3 deposits are commonly found in immunoglobulin A (IgA) nephropathy. Renal gene expression and protein synthesis of complement components have been shown in settings of tissue inflammation. In this study, the pathogenetic involvement of locally produced C3 in IgA nephropathy was analyzed. C3 gene expression was analyzed by reverse transcription, polymerase chain reaction, and in situ hybridization techniques. C3 mRNA was detected in 56% of cases, with a significantly higher percentage in patients with moderate-to-severe lesions than in those with mild lesions (P < 0.01). By in situ hybridization, C3 transcript was predominantly expressed by tubular cells and some interstitial cells. C3 mRNA was also observed on glomerular parietal epithelial cells. Immunoreactive native C3 was detected on cortical tubuli by an anti-C3c immunoalkaline-phosphatase technique. A significant correlation was found between renal C3 transcription and glomerulosclerosis, intracapillary proliferation (both P < 0.005) and markers of interstitial damage, including tubular atrophy (P < 0.05), interstitial infiltration (P < 0.05), and fibrosis (P < 0.005). Proteinuria (P < 0.05), but not serum creatinine, at the time of renal biopsy correlated with C3 mRNA. In conclusion, it was demonstrated that the C3 gene was expressed primarily in proximal tubular cells and occasionally in glomerular crescents, and that its expression correlated with clinical and histologic markers of severity and poor outcome of IgA nephropathy. Thus, a pathogenetic involvement of the local transcription and translation of the C3 gene in IgA nephropathy was suggested.
Assuntos
Complemento C3/genética , Expressão Gênica , Glomerulonefrite por IGA/genética , Córtex Renal/fisiopatologia , Adolescente , Adulto , Criança , Progressão da Doença , Feminino , Imunofluorescência , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Imunoglobulinas/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Rim/patologia , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismoRESUMO
Monocyte chemotactic peptide-1 (MCP-1) belongs to a large family of cytokines known as chemokines. It is a potent mediator of inflammatory response and is thought to play a major role in recruiting monocytes into the site of inflammation. Mixed cryoglobulinemia is a systemic vasculitis characterized in 10 to 30% of the cases by renal involvement. Monocyte infiltration into the glomerulus, and in the periglomerular and perivascular areas is a common histopathological feature of this form of glomerulonephritis. We sought to determine, by in situ hybridization and immunohistochemistry, the renal gene and protein expression of MCP-1 in cryoglobulinemic glomerulonephritis compared to normal kidney, and to correlate it with macrophage infiltration. Kidney biopsy specimens were obtained from 9 patients with cryoglobulinemic glomerulonephritis and 9 control kidneys. The distribution and intensity of MCP-1 gene and protein expression, and the macrophage infiltration (CD68 positive cells) were evaluated and quantitated by a computerized image analysis system. In normal kidneys, MCP-1 was weakly expressed, both at the gene as well as at the protein level. In diseased kidneys, a statistically significant (P < 0.001) up-regulation of MCP-1 gene and protein expression was found, particularly within the areas of tubulointerstitial damage and the glomeruli. By means of CD68 positive cells, a significant correlation (P < 0.001) was found between glomerular, tubulointerstitial macrophage infiltration and MCP-1 expression. Moreover, by combining immunohistochemistry and in situ hybridization, we observed the presence of CD68 positive cells mainly, if not exclusively, around the cells expressing MCP-1 mRNA. Interestingly, a striking increase in MCP-1 urinary concentration was found in cryoglobulinemic patients. In conclusion, our data suggest that MCP-1 may play a major role in modulating the inflammatory process observed in cryoglobulinemic glomerulonephritis.
Assuntos
Quimiocina CCL2/genética , Crioglobulinemia/fisiopatologia , Glomerulonefrite Membranoproliferativa/patologia , Monócitos/imunologia , Adulto , Idoso , Biópsia , Northern Blotting , Quimiocina CCL2/análise , Quimiocina CCL2/urina , Crioglobulinemia/imunologia , Feminino , Glomerulonefrite Membranoproliferativa/imunologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Monócitos/química , RNA Mensageiro/metabolismoRESUMO
Tubulointerstitial damage is a common histopathological feature of acute and chronic renal diseases and a prognostic indicator of renal function outcome. Monocytes infiltrating the interstitium, through the release of cytokines and/or growth factors, may play a key role in the pathogenesis of tubulointerstitial damage. Monocyte chemotactic peptide-1 (MCP-1) is a specific and powerful chemoattractant and activating factor for monocytes. This study investigated MCP-1 expression and its correlation with monocyte infiltration and tubulointerstitial damage in biopsies of patients with acute interstitial nephritis (AIN) and a chronic glomerulonephritis, namely immunoglobulin. A nephropathy (IgAN), often characterized by tubulointerstitial involvement. Six patients with AIN and 20 patients with IgAN, nine with mild (G1 to 2) and 11 with moderate to severe histologic lesions (G3 to 5), were studied. MCP-1 gene and protein expression were evaluated by in situ hybridization and immunohistochemistry. Infiltrating CD68-positive cells were identified as monocytes. MCP-1, weakly expressed in normal kidneys, was clearly upregulated in AIN biopsies. The gene and the protein expression were primarily localized in tubular and glomerular parietal epithelial cells, as well as in infiltrating mononuclear cells. In IgAN, a striking increase in MCP-1 mRNA and protein expression was observed only in the biopsies with moderate to severe lesions, with a pattern of expression similar to AIN. The MCP-1 expression strictly correlated with monocyte infiltrates and tubulointerstitial damage. In addition, the urinary excretion of this chemokine was studied in 17 IgAN patients. MCP-1 protein concentration was higher, compared with healthy subjects, in IgAN patients, especially in the G3 to 5 group, and directly correlated with the renal MCP-1 gene expression. In conclusion, these data suggest that production of MCP-1 in the tubulointerstitial compartment may play a key role in modulating monocytes influx and, consequently, tubulointerstitial damage.